Eur J Clin Pharmacol DOI 10.1007/s00228-014-1655-4
REVIEW ARTICLE
Is the decision on the use of biosimilar growth hormone based on high quality scientific evidence? – a systematic review Linda Fryklund & Martin Ritzén & Göran Bertilsson & Marianne Heibert Arnlind
Received: 29 November 2013 / Accepted: 28 January 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Background The authors carried out a systematic and critical review of the scientific literature regarding the possible development of neutralising antibodies developed in patients treated with growth hormone biosimilars (defined as a drug expected to be similar to the originator or original pharmaceutical -European Medicines Agency) as compared to the reference drug. As a consequence, we discovered two major issues, namely, the poor quality of the comparative clinical trials and the poor quality of the antibody assays used during the trials. Methods The literature review was performed according to the principle of the Cochrane Collaboration and SBU. The electronic literature search included the databases PubMed, EMBASE and The Cochrane Library up to December 2012. Two independent reviewers assessed abstracts and full-text articles. Results The search identified 1,553 abstracts related to the subject. Only six articles contained data on biosimilar growth hormone or antibody results obtained with appropriate Electronic supplementary material The online version of this article (doi:10.1007/s00228-014-1655-4) contains supplementary material, which is available to authorized users. L. Fryklund : M. Ritzén : G. Bertilsson : M. H. Arnlind SBU, Box 3657, 103 59 Stockholm, Sweden L. Fryklund e-mail:
[email protected] M. Ritzén e-mail:
[email protected] G. Bertilsson e-mail:
[email protected] M. Ritzén KBH, Karolinska Institutet, 171 77 Stockholm, Sweden M. H. Arnlind (*) LIME/MMC, Karolinska Institutet, 171 77 Stockholm, Sweden e-mail:
[email protected]
methods. None of the studies fulfilled the criteria for high quality randomised controlled trials. Qualitative rather than quantitative assays were used for monitoring antibody formation. Conclusions It is our firm opinion , that since biosimilars are not identical, emphasis must be placed on the quality of the comparative clinical trials performed and the quality of the analytical studies in order to guarantee patient safety. Clinical trials should follow established quality rules for controlled comparative randomised clinical trials. A whole set of new guidelines is required. Keywords Growth hormone . Biosimilar . Efficacy . Antibodies . Systematic review . Quality . Clinical Abbreviations E. coli Escherichia coli INN International Nonproprietary Name PICO Population Intervention Comparison Outcome Somatropin INN for human growth hormone RCT Randomised controlled trials
Introduction Twenty years on, patents have expired and the drug approval authorities such as the European Medicines Agency (EMA) and the Federal Drug Agministration -USA (FDA) have wished to see a second generation of protein biopharmaceuticals in analogy to the situation with generics based on small molecules. The above named authorities, while recognizing that a true generic type copy cannot be made since neither the production methods, nor the recombinant organism plasmid and analytical methods are the same, have assumed that as long as the drug substance is the same, then therapeutic
Eur J Clin Pharmacol
equivalence is comparable. Therefore, guidelines have been developed for biosimilars [1]. The requirement for the manufacture of the biosimilar are as stringent as for the reference drug, the big difference being that the clinical trial programme is vastly simplified and it is enough to show therapeutic equivalence in a single comparative clinical trial for each indication that has already been approved for the reference product [1]. In the case of biosimilars, the host organism does not necessarily have to be the same strain of E. coli (Genotropin compared with Omnitrope) or the same class of organism [2]. For the recent history of protein pharmaceuticals see Appendix 2. This review is based in part on a comprehensive systematic review, published in Swedish by the Swedish Council on Health Technology Assessment, SBU, of immunological reactions induced by treatment with biosimilar somatropin [3]. SBU is an independent government agency for the critical evaluation of methods for preventing, diagnosing and treating health problems. The purpose of this systematic literature review was to investigate whether the clinical trial data in the public domain (published peer reviewed) provides evidence that the human growth hormone biosimilar Omnitrope (available in Sweden) originator product Genotropin and Valtropin (approved by the European Medicines Agency, EMA) not yet marketed in Sweden, and reference drug Humatrope, fulfil the requirements for interchangeability. As a consequence we discovered two major issues, namely, the poor quality of the comparative clinical trials and the poor quality of the antibody assays used during the trials.
NorditropiN*[tiab] OR NutropinAq*[tiab] OR Saizen*[tiab] OR Zomacton*[tiab] OR Nutropin*[tiab] OR Genotonorm[tiab]. The complete search strategy can be provided on request. Language was restricted to English, Swedish and Norwegian. The primary question in the present systematic literature review was whether treatment with the growth hormone biosimilars resulted in antibody formation that might influence efficacy and safety. Inclusion and exclusion criteria Only studies of somatropin produced by biosynthetic methods have been assessed, not the somatotropin preparations derived from human pituitary glands, since these drugs are no longer on the market. The selection of studies was based on the following criteria and PICO elements were used to describe the population, intervention, control and outcome [4]: Population: &
Children and adults who are prescribed growth hormone Intervention:
& &
A - Treatment with recombinant human growth hormone (somatropin) for an approved indication B - Switching between the original and/or biosimilar somatropin Control:
Methods
&
Literature search and selection of articles
&
For A - placebo, no treatment, other original somatropin, somatotropin or biosimilar somatropin For B - Patients without changing somatotropin preparations
The systematic literature review Outcome: The Cochrane Collaboration definition of a systematic review has been used, namely “A systematic review attempts to identify, appraise and synthesise all the empirical evidence that meets pre-specified eligibility criteria to answer a given research question. Researchers conducting systematic reviews use explicit methods aimed at minimising bias, in order to produce more reliable findings that can be used to inform decision making.” (www.thecochranelibrary.com). The electronic literature search included the databases PubMed, EMBASE, and The Cochrane Library up to December 2012. The text words and MeSH terms were: Human Growth Hormone[Mesh] OR recombinant human growth hormone[tiab] OR somatropin*[tiab] OR RhGH[tiab] OR Omnitrope*[tiab] OR Valtropin*[tiab] OR Genotropin*[tiab] OR Humatrope*[tiab] OR
& & & &
Increase in height, metabolic effects (randomised controlled trials, RCTs) only in comparisons between biosimilars and/or original somatropin The occurrence of allergic/immunologic reactions The presence of neutralising antibodies, i.e., antibodies that block the physiological function of the administered hormone The presence of antibodies to growth hormone
Quality rating of individual studies The quality of each study included was rated as high, moderate or low according to the Swedish Council on Health
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Technology Assessment (SBU) standard checklist determining the extent to which the studies met the basic quality criteria, e.g., study design, study population, outcome measures and the analytical methods used [5–7]. Only studies with a high or moderate quality were considered good enough to be used for the systematic review, see Fig. 1, flow charts. Of the 24 studies, five studies were rated as low quality, one rated moderate and none was rated as high quality. Because only a single study was found to have at least moderate quality, we also tabulated the five low-quality studies.
had no information on immunology or were published in nonpeer-reviewed supplements. A list of excluded articles with the main reason for exclusion can be found as supplementary material on the Journal’s web site. Six publications were considered relevant for the questions asked. These are summarised in Table 1. Among those, two randomised controlled studies were found where a biosimilar somatropin was compared with an original; one with Valtropin [2] and one with Omnitrope [8]. Valtropin
Results A flow chart showing the results of the literature search and the outcome of the selection procedures is given in Fig. 1. The electronic searches resulted in 1,542 abstracts (Fig. 1). Two reviewers (MR and LF) read these abstracts independently. An article was read in full text if at least one of the two reviewers considered an abstract to be potentially relevant. Hand search and non-peer reviewed literature identified 11 articles and were also included in this review. The prespecified inclusion/exclusion criteria are given in the Methods section. Altogether, 24 articles were read in full text and assessed independently by the same two reviewers. Of 24 articles, 18 did not fulfil the inclusion criteria and were excluded from further analysis. The reasons for exclusions were that they were reviews (no original data), described somatropin preparations not yet or any longer on the market, Records identified through database searching 1 542 Additional records identified through other sources 11
Records excluded 1 529
Full-text articles assessed for eligibility 24
Full-text articles excluded, with reasons 18 Studies included in qualitative synthesis 6
Studies with low study quality 5
Fig. 1 Flow chart
Studies with moderate study quality 1
Studies with high study quality 0
Peterkova et al. (2007) reported a randomised controlled study, comparing the biosimilar somatropin Valtropin with the reference drug Humatrope (Lilly) during 12 months of treatment of GH deficient prepubertal children. GH deficiency was defined as reaching a maximum GH level 1 SD below mean), born full term with birth weight >2500 g. Children with chronic systemic disease, that could influence growth were excluded. Male/female: 49/40
89 treatment naïve children with deficiency GHD (GHmax
